Career Summary

Biography

I received my PhD from City University of Hong Kong in 2002. After my postdoctoral training with Prof. Rudolf Wu, I continued to work in the same institution as a Lecturer until joining the University of Newcastle in 2009. I am now an academic in the Discipline of Environmental Science and Management in the School of Environmental & Life Sciences (SELS).

My primary research interests are in the Molecular Toxicology of Environmental Stressors and Chemicals.

In particular, I am interested in (1) understanding the molecular mechanisms of endocrine disruption caused by hypoxia and environmental chemicals and (2) developing cell- and animal-based assays for the screening and detection of endocrine-disrupting chemicals (EDCs). Overall, my research covers both basic science aimed at understanding the fundamental mechanisms of environmental toxicity and applied science concerned with the development of diagnostic tools for assessing and monitoring environmental toxicity. Outlined below is a summary of my recent research activities and findings:

1. Environmental Obesogens

The prevalence of obesity has been dramatically increasing worldwide during the last several decades. In recent years, there is growing epidemiological evidence indicating a positive correlation between the exposure of human population to EDCs and body weight, suggesting a possible role of EDCs in increasing obesity rates. The "obesogen hypothesis" is an emerging view proposing that exposure to a subset of these chemicals (obesogens) disrupts the weight-control mechanisms and ultimately increases obesity. To date, most of the known obesogens are those directly increasing adipogenesis and lipid accumulation, while the ones that contribute to diet-induced obesity (DIO) are understudied.

Leptin is an adipocyte-derived hormone that represses appetite and increases energy expenditure. Leptin inhibits appetite by decreasing the activity of the orexigenic NPY/AgRP/GABA neurons and increasing the activity of the anorexigenic POMC/CART neurons in the hypothalamus. Leptin action is exerted through its binding to the leptin receptor (OB-R) expressed on the surface of these neurons. Recent research showed that the disruption of OB-R activation (after treatment with leptin antagonists) during early development can lead to adult leptin resistance. Leptin resistance is a medical condition in which individuals are weakly responsive or unresponsive to high circulating levels of leptin and regarded as an important predisposing factor for DIO. Based on this existing knowledge, we hypothesise that early-life exposure to environmental chemicals that act as leptin antagonists can enhance the development of leptin-resistance and DIO in adults.

In collaboration with my co-worker Dr Richard Kong at City University of Hong Kong, a pilot screening program was recently initiated to identify environmental chemicals that act as leptin antagonists using biophysical and cell-based assays. Further effort will be made to assess the ability of the identified candidates to induce the developmental programming of adult leptin resistance and DIO using zebrafish (an important human disease model). This project is anticipated to provide important information regarding the contribution of developmental programming to the obesity epidemic, through assessing the role of early-life exposure of environmental chemicals in the development of adult leptin resistance and obesity. Since the rising prevalence of obesity has been recently noticed in livestock, pets, and wild animals, the knowledge about the mechanism of action of environmental obesogens and the technologies developed in this research could also be applied to a much broader range of biota beyond humans. Eventually, the outcome of this research may aid in devising new regulations on the safety of animal feed and the release of obesogenic chemicals to the environment.

2. Estrogen-mediated Vitellogenesis in Oysters

Oysters respond to EDC mixtures with the induction of the female egg yolk protein, vitellogenin (Vtg), availing a biomarker which indicates the presence of estrogenic contaminants in sewage effluent receiving waters. Despite this, the precise mechanism through which estrogens exert their action to induce vitellogenesis is unknown. Estrogen receptors (ERs) with homology to vertebrate ERs have been identified in selected molluscan taxa, yet those found to date do not bind or are unresponsive to estrogen. We hypothesise that estrogens may bind to receptors yet to be identified in Mollusca, with lower structural similarity to vertebrate-like ERs, and such receptors act as estrogen-dependent transcriptional regulators of vitellogenin expression. In an effort to investigate this possibility, Dr Geoff MacFarlane (UoN) and I initiated a project to isolate and characterise novel “functional” ERs from the native Sydney rock oyster (Saccostrea glomerata). Our recent progress indicated that an invertebrate-like ER isolated from the Sydney rock oyster ovarian tissues shares a similar ligand (estrogen) binding pocket with that of the human ER and is expressed in response to estrogenic compounds. Further effort will be directed at clarifying its functional roles in mediating vitellogenesis and gonadal development and its epigenetic regulation in response to the exposure to estrogenic compounds. At the application level, this research will provide important information (an ER pathway specific to invertebrates) for the development of bioassays for screening xenoestrogens with ecotoxicological relevance to molluscs.

3. Fish Hypoxia

Previously, my co-workers and I have demonstrated for the first time that hypoxia can disrupt sex differentiation via modulation of gene expression for estrogen biosynthesis, leading to a male-biased sex ratio in zebrafish (Shang et al. 2006). This work has highlighted the alarming impacts of aquatic hypoxia on fish reproduction and sustainability, and thus attracted worldwide attention, as exemplified by cover stories written by Science and Nature as well as reports by CNN and ABC. This study has been cited 60 times since its publication in 2006. Later studies also provided scientific evidence that the transcription factor hypoxia-inducible factor-1 (HIF-1) regulates a number of genes involved in fish growth and reproduction in response to hypoxia (Yu et al. 2006a, 2008; Chu et al. 2010). To assess the applicability and specificity of HIF-1-regulated gene expression as biomarkers for monitoring aquatic hypoxia, we also made efforts to decipher the crosstalk between the xenobiotic transformation pathway and the HIF-1 pathway. Intriguingly, we demonstrated that the existence of xenobiotics can enhance HIF-1-mediated gene expression via increasing the cellular levels of reactive oxygen species (ROS), indicating that the presence of environmental xenobiotics must be considered when interpreting HIF-1-based hypoxia biomarker results (Yu et al. 2008). In 2012, my co-workers (Kong & Wu) and I obtained a seed fund ($US 115,384) from the State Key Laboratory in Marine Pollution, China to study the interactive effects of climate change and hypoxia on fish sex determination.

4. Fish Leptin

The study of obesity and appetite control in fish models is an emerging field of research. In the last few years, my co-workers and I highlighted striking similarities in the function and regulation of leptin between fish and mammals. Our recent work suggests that leptin elevation under hypoxic conditions is a pathophysiological response common to both zebrafish and mammalian models (Chu et al. 2010). In another prior study, we reported for the first time the characterization of a fish long-form leptin receptor that contains all the signature motifs and domains found in the mammalian leptin receptors (Wong, Yu et al. 2007), implying the function of leptin receptor is conserved in both fish and mammals. Recently, using gain-or-loss gene function techniques, we demonstrated that leptin is the molecular link between hypoxia and endocrine disruption, leading to the suppression of the aromatase gene (cyp19a) and hence estrogen production in fish (Yu et al. 2012). Taken together, these findings provide novel insights into the molecular mechanism of endocrine disruption under hypoxia. This research successfully attracted $US 108,974 funding from Hong Kong General Research Fund (GRF) in 2011.

5. In-vitro bioassays for EDCs

For years, I have been collaborating with Prof. John Giesy (Canada Research Chair in Environmental Toxicology, University of Saskatchewan) on the development and validation of a H295R cell line screening test to evaluate toxicant-induced effects on steroid biosynthesis (steroidogenesis)—the H295R Steroidogenesis Assay (Gracia et al. 2004; Zhang et al. 2005; Gracia et al. 2006; Xu et al. 2006; Gracia et al. 2007; He et al. 2008; Song et al. 2008). This assay has been successfully used to assess the endocrine-disrupting potential and the mechanisms of action of various chemicals and environmental samples. This assay is currently being developed as part of Tier 1 of the US EPA Endocrine Disruptor Screening Program and an Organization for Economic Cooperation and Development (OECD) test method validation program.

6. In-vivo bioassays for EDCs

We recently demonstrated that induction of hepatic choriogenin H (ChgH, a fish egg-shell protein precursor) mRNA expression in male marine medaka can serve as a highly sensitive biomarker for environmental estrogens (its sensitivity is even better than vitellogenin) (Yu et al. 2006b; Cheng et al. 2008). This novel discovery led us to develop a ChgH-GFP transgenic marine medaka for monitoring environmental estrogens in marine water. Our recent progress indicated that this sentinel fish can detect 17β-estradiol (E2) at nominal concentrations as low as 1 μg/L. To make quantification of in vivo GFP expressed in developing fish embryos feasible, we previously developed an automatic 4D (3D plus time) acquisition system and the imaging processes of deconvolution and thresholding (Yu et al. 2006c). This 4D imaging system provides a simple but powerful means to quantify in vivo gene expression in a developmental toxicology context. The technologies have been successfully commercialised as environmental and food safety consultancy service in Hong Kong (Vitargent (International) Biotechnology Ltd).

Research ExpertiseEcotoxicology Molecular toxicology Obesogen screening Embryotoxicity assays Development of bioassays for EDC screening and detection

Highlighted grants and funding

Obesity is a global epidemic with rising trends in Asian countries, including China and Hong Kong. Because obesity is closely associated with chronic diseases, such as type 2 diabetes and cardiovascular diseases, the increase in obesity corresponds to a rise in mortality rates. There is growing epidemiological evidence indicating a positive correlation between the exposure of human population to endocrine-disrupting chemicals (EDCs, chemicals that affect hormone systems) and body weight, suggesting a possible role of EDCs in increasing obesity rates. The “obesogen hypothesis” proposes that exposure to a subset of these chemicals (obesogens) disrupts the body’s weight-control mechanisms and ultimately increases obesity. To date, most of the widely known obesogens are those that directly increase adipogenesis and lipid accumulation, while the ones which contribute to overeating (a major non-genetic cause of obesity) are understudied.

Leptin is an adipocyte-derived hormone that plays a key role in regulating food intake and inhibits appetite by decreasing the activity of the orexigenic NPY/AgRP/GABA neurons and increasing the activity of the anorexigenic POMC/CART neurons in the hypothalamus. Leptin action is exerted through its binding to the leptin receptor (OB-R) expressed on the surface of these neurons. Interestingly, chronically elevated leptin levels in “non-genetic obesity” individuals fail to cause appetite inhibition. This apparent leptin ineffectiveness (leptin resistance) is considered an important predisposing factor for diet-induced obesity (DIO). Although the concept of leptin resistance is widely accepted, its underlying mechanisms remain elusive. However, mounting evidence suggests that defective leptin transport across the blood-brain barrier (BBB) and disrupted hypothalamic leptin signaling are the potential causes for leptin resistance. Because leptin receptor (OB-R) plays an important role in regulating leptin transport and leptin signaling, it is highly likely that any disruption in OB-R activation will lead to leptin resistance. We hypothesize that certain environmental chemicals could act as leptin antagonists to enhance or promote obesity (as a result of leptin resistance) by the disruption of OB-R activity.

This study aims to conduct a screening program against a chemical library of representative environmental compounds (using biophysical and cell-based assays) to identify environmental chemicals that act as leptin antagonists. Chemicals identified by the screening program will be further tested in zebrafish to determine whether early developmental exposures to these chemicals could potentially lead to leptin resistance and DIO in adult life. We anticipate that the results of the proposed study will provide important new insights into the role of exposure to environmental chemicals in the development of obesity and thereby open new perspectives for the formulation of effective preventive strategies against obesity.

The ultimate goal of this project is to provide novel insights into the mechanistic role of leptin in endocrine disruption observed in hypoxic fish. Hypoxia (<2mg O2 L−1) arising as a result of euthrophication affects vast stretches of aquatic ecosystems worldwide and often leads to population decline and changes in community structure by eliminating oxygen-sensitive species. Endocrine disruption is one of the major causes of reproductive impairment observed in hypoxic fish. Our recent study demonstrated that hypoxia can alter both the levels and the balance of testosterone and estradiol, resulting in retarded gonadal development and altered phenotypic sex ratio in zebrafish. Reproductive impairments with concomitant perturbation of estrogens and androgens were similarly reported in several other fish species exposed to hypoxia. However, the mechanisms of such hypoxia-induced disruption of sex steroids are yet to be elucidated. One of the mechanisms of endocrine disruption is interference with steroidogenesis. In a previous study, we demonstrated that expression of cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A) is down-regulated in hypoxic zebrafish embryos. Down-regulation of expression of CYP11A as well as the steroidogenic acute regulatory protein (StAR) gene has also been observed in human adrenocortical carcinoma H295R cells after short-term exposures to hypoxic conditions. Since both StAR and CYP11A represent the first and rate-determining steps of the steroidogenesis cascade, their suppression could contribute to the decreased sex steroid production observed in hypoxic fish. However, the regulatory mechanisms underlying hypoxia-mediated suppression of StAR and CYP11A remain elusive. The hormone leptin, apart from being a central regulator of food intake and metabolism, plays a role in modulating reproduction in mammals. This modulatory effect is likely due in part to the direct inhibitory effect of leptin on adrenal and gonadal steroidogenesis, mostly through attenuation of StAR and CYP11A gene expression. The molecular mechanisms accounting for this attenuation is still unclear, although steroidogenic factor 1 (SF1), a transcription factor essential for activation of multiple steroidogenic genes, may be involved. Hypoxia has been shown to increase leptin expression and secretion in various in vivo and in vitro mammalian systems, and the involvement of hypoxia-inducible factor 1 (HIF-1) in these responses was suggested. Our team recently demonstrated that HIF1-α overexpression can also elevate leptin gene expression in zebrafish embryos. Based on these observations, we hypothesize that the suppressive effects of hypoxia on steroidogenic gene expression in early zebrafish development is at least in part due to HIF-1α-enhanced leptin expression.

Funding body: University Grants Committee (Hong Kong)

Funding body

University Grants Committee (Hong Kong)

Project Team

Richard Yuen-chong Kong

Scheme

Research Grants Council - General Research Fund

Role

Investigator

Funding Start

2011

Funding Finish

2014

GNo

Type Of Funding

International - Competitive

Category

3IFA

UON

N

20161 grants / $144,654

Obesity is a global epidemic with rising trends in Asian countries, including China and Hong Kong. Because obesity is closely associated with chronic diseases, such as type 2 diabetes and cardiovascular diseases, the increase in obesity corresponds to a rise in mortality rates. There is growing epidemiological evidence indicating a positive correlation between the exposure of human population to endocrine-disrupting chemicals (EDCs, chemicals that affect hormone systems) and body weight, suggesting a possible role of EDCs in increasing obesity rates. The “obesogen hypothesis” proposes that exposure to a subset of these chemicals (obesogens) disrupts the body’s weight-control mechanisms and ultimately increases obesity. To date, most of the widely known obesogens are those that directly increase adipogenesis and lipid accumulation, while the ones which contribute to overeating (a major non-genetic cause of obesity) are understudied.

Leptin is an adipocyte-derived hormone that plays a key role in regulating food intake and inhibits appetite by decreasing the activity of the orexigenic NPY/AgRP/GABA neurons and increasing the activity of the anorexigenic POMC/CART neurons in the hypothalamus. Leptin action is exerted through its binding to the leptin receptor (OB-R) expressed on the surface of these neurons. Interestingly, chronically elevated leptin levels in “non-genetic obesity” individuals fail to cause appetite inhibition. This apparent leptin ineffectiveness (leptin resistance) is considered an important predisposing factor for diet-induced obesity (DIO). Although the concept of leptin resistance is widely accepted, its underlying mechanisms remain elusive. However, mounting evidence suggests that defective leptin transport across the blood-brain barrier (BBB) and disrupted hypothalamic leptin signaling are the potential causes for leptin resistance. Because leptin receptor (OB-R) plays an important role in regulating leptin transport and leptin signaling, it is highly likely that any disruption in OB-R activation will lead to leptin resistance. We hypothesize that certain environmental chemicals could act as leptin antagonists to enhance or promote obesity (as a result of leptin resistance) by the disruption of OB-R activity.

This study aims to conduct a screening program against a chemical library of representative environmental compounds (using biophysical and cell-based assays) to identify environmental chemicals that act as leptin antagonists. Chemicals identified by the screening program will be further tested in zebrafish to determine whether early developmental exposures to these chemicals could potentially lead to leptin resistance and DIO in adult life. We anticipate that the results of the proposed study will provide important new insights into the role of exposure to environmental chemicals in the development of obesity and thereby open new perspectives for the formulation of effective preventive strategies against obesity.

20111 grants / $102,253

The ultimate goal of this project is to provide novel insights into the mechanistic role of leptin in endocrine disruption observed in hypoxic fish. Hypoxia (<2mg O2 L−1) arising as a result of euthrophication affects vast stretches of aquatic ecosystems worldwide and often leads to population decline and changes in community structure by eliminating oxygen-sensitive species. Endocrine disruption is one of the major causes of reproductive impairment observed in hypoxic fish. Our recent study demonstrated that hypoxia can alter both the levels and the balance of testosterone and estradiol, resulting in retarded gonadal development and altered phenotypic sex ratio in zebrafish. Reproductive impairments with concomitant perturbation of estrogens and androgens were similarly reported in several other fish species exposed to hypoxia. However, the mechanisms of such hypoxia-induced disruption of sex steroids are yet to be elucidated. One of the mechanisms of endocrine disruption is interference with steroidogenesis. In a previous study, we demonstrated that expression of cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A) is down-regulated in hypoxic zebrafish embryos. Down-regulation of expression of CYP11A as well as the steroidogenic acute regulatory protein (StAR) gene has also been observed in human adrenocortical carcinoma H295R cells after short-term exposures to hypoxic conditions. Since both StAR and CYP11A represent the first and rate-determining steps of the steroidogenesis cascade, their suppression could contribute to the decreased sex steroid production observed in hypoxic fish. However, the regulatory mechanisms underlying hypoxia-mediated suppression of StAR and CYP11A remain elusive. The hormone leptin, apart from being a central regulator of food intake and metabolism, plays a role in modulating reproduction in mammals. This modulatory effect is likely due in part to the direct inhibitory effect of leptin on adrenal and gonadal steroidogenesis, mostly through attenuation of StAR and CYP11A gene expression. The molecular mechanisms accounting for this attenuation is still unclear, although steroidogenic factor 1 (SF1), a transcription factor essential for activation of multiple steroidogenic genes, may be involved. Hypoxia has been shown to increase leptin expression and secretion in various in vivo and in vitro mammalian systems, and the involvement of hypoxia-inducible factor 1 (HIF-1) in these responses was suggested. Our team recently demonstrated that HIF1-α overexpression can also elevate leptin gene expression in zebrafish embryos. Based on these observations, we hypothesize that the suppressive effects of hypoxia on steroidogenic gene expression in early zebrafish development is at least in part due to HIF-1α-enhanced leptin expression.

Funding body: University Grants Committee (Hong Kong)

Funding body

University Grants Committee (Hong Kong)

Project Team

Richard Yuen-chong Kong

Scheme

Research Grants Council - General Research Fund

Role

Investigator

Funding Start

2011

Funding Finish

2014

GNo

Type Of Funding

International - Competitive

Category

3IFA

UON

N

20092 grants / $15,000

Endocrine disrupting chemicals (EDCs) can affect the normal growth and reproduction of the wildlife. Currently, bioassays to detect EDCs are largely based on the potential for direct interaction of chemicals with steroid hormone receptors, thus ignoring many chemicals that are able to interfere with the endocrine system by other non-receptor-mediated mechanisms. One of the important mechanisms by which EDCs cause endocrine disruption is via interfering with steroid synthesis (steroidogenesis). The nematode Caenorhabditis elegans has recently emerged as a useful invertebrate system for ecotoxicological monitoring of environmental chemicals. In an attempt to develop C. elegans bioassays for monitoring steroidogenesis disrupting chemicals, this project will identify novel molecular targets of EDCs in the biosynthetic pathway of dafachronic acids, hormones that are required for normal growth and reproductive development in C. elegans. The outcome of this project would advance the technology to detect endocrine disruption activities present in environmental samples.

Funding body: Faculty of Science and Information Technology,The University of Newcastle

Funding body

Faculty of Science and Information Technology,The University of Newcastle

Research Supervision

Number of supervisions

Completed1

Current3

Total current UON EFTSL

PhD1.6

Current Supervision

Commenced

Level of Study

Research Title / Program / Supervisor Type

2016

PhD

Assessing of Potential Estrogenic Effects on Freshwater Mussel (Hyridelladepressa) in New South Wales, AustraliaPhD (Environmental Sc), Faculty of Science and Information Technology, The University of NewcastleCo-Supervisor

2014

PhD

Molecular cloning and characterisation of insulin-like growth factor binding protein (IGFBP) genes in the Sydney rock oysterPhD (Environmental Sc), Faculty of Science and Information Technology, The University of NewcastlePrincipal Supervisor

Past Supervision

Year

Level of Study

Research Title / Program / Supervisor Type

2016

PhD

Influence of Metal Exposure History on Metal Tolerance in the Sydney Rock Oyster (Saccostrea Glomerata)PhD (Biological Sciences), Faculty of Science and Information Technology, The University of NewcastleCo-Supervisor

Research Collaborations

The map is a representation of a researchers co-authorship with collaborators across the globe. The map displays the number of publications against a country, where there is at least one co-author based in that country. Data is sourced from the University of Newcastle research publication management system (NURO) and may not fully represent the authors complete body of work.